obesity reviews doi: 10.1111/j.1467-789X.2007.00406.

Complications of Obesity

The impact of obesity on female reproductive function

M. Metwally, T. C. Li and W. L. Ledger

Academic Unit of Reproductive Medicine, the Summary

Jessop Wing, Sheffield, S10 4ED, UK
Received 24 April 2007; revised 12 July 2007;
accepted 24 August 2007
Address for correspondence: M Metwally,
Academic Unit of Reproductive Medicine, the
Jessop Wing, Sheffield S10 4ED, UK. E-mail:
m.metwally@shef.ac.uk
Obesity may be described as the new worldwide epidemic, and its serious impact
on morbidity and mortality are well known. As more and more women become
obese, the reproductive problems associated with obesity present an ever-growing
challenge to physicians involved in their fertility care. The spectrum of reproduc-
tive problems associated with obesity encompasses a wide range of disorders
including infertility problems, miscarriage and pregnancy complications. In this
review, we aim to discuss the impact of obesity on the various aspects of female
reproductive function with focus on the clinical aspects of fertility problems in
obese women. We finally comment on the available therapeutic options available
to this group of women.

Keywords: Adipokines, female reproduction, infertility, obesity.

obesity reviews (2007) 8, 515523

an inhibitory effect on developing ovarian follicles (3).

Introduction
The prevalence of obesity is constantly on the rise and
constitutes a major worldwide epidemic. As the prevalence
of obesity is increasing, so is the number of women in the
reproductive age who are becoming overweight and obese
(1). As a result of this spreading epidemic, it is important
that physicians involved in the care of this group of women
are fully aware of the spectrum of reproductive disorders
associated with obesity. This review aims to discuss the
impact of obesity on the various aspects of female repro-
ductive function with focus on the clinical aspects of
fertility problems in obese women.
Obesity and gonadal function
The relationship between adipose tissue and the gonads is
bilateral. Adipose tissue influences gonadal function by
secretion of adipokines, such as leptin, adiponectin, ghrelin
and resistin. By far, the most investigated of these is leptin.
The reproductive functions of leptin include a role in
regulating early embryo cleavage and development (2), a
stimulatory effect on the hypothalamic-pituitary axis and
Obesity is associated with elevated serum and follicular
fluid leptin concentrations. Leptin by acting on specific
follicular cell receptors may mediate a reduction of insulin-
induced steroidogenesis in both granulosa and theca cells
(4). Leptin has also been found to inhibit luteinising
hormone (LH)-stimulated oestradiol production by the
granulosa cells. These effects may partially explain the poor
reproductive performance in obese women (3).
Adiponectin is the most abundant gene product in adipose
tissue and accounts for 0.01% of total plasma protein.
Adiponectin levels decrease in obesity and are negatively
associated with plasma insulin (5). Adiponectin may thus
provide an important link between obesity, insulin resis-
tance and the resulting state of hyperandrogenism.
The reproductive roles of other adipokines such as resis-
tin and ghrelin in humans are still a matter of controversy
and more research is needed.
One of the key effects of obesity on steroid hormones is
hyperandrogenism secondary to hyperinsulinaemia. Hyper-
insulinaemia may be due to the effects of decreased levels of
adiponectin, increased levels of resistin (5,6) or possibly
a polymorphism characterized by glycine-to-arginine

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substitution at codon 972 (Gly972Arg) of the insulin recep-

tor substrate (7). Hyperandrogenaemia is consequently
caused by inhibition of the hepatic production of sex
hormone-binding globulin and insulin-like growth factor
binding protein-I and stimulation of ovarian P450c17a
activity (8).
Reproductive disorders associated
with obesity
Infertility
Several studies have shown an increased risk of anovulatory
infertility in obese women, and their findings are summa-
rized in Table 1. Anovulation is a result of hyperandro-
genism through the promotion of granulosa cell apoptosis
(9). Other possible causes of infertility include an increased
peripheral conversion of androgens to oestrogen leading to
an increased negative feedback on gonadotrophin secretion
(6), possible adverse effects on the endometrium and devel-
oping oocyte as a result of increased androgens (6) and an
adverse effect on the granulosa and theca cells as a result of
increased levels of circulating leptin (4).
Polycystic ovarian syndrome (PCOS), a condition also
commonly associated with anovulatory infertility, is closely
related to obesity; however, it is unclear whether obesity
leads to PCOS or vice versa.
The two conditions share several pathophysiological
characteristics namely insulin resistance (10) and hyperan-
drogenaemia, and it may be that peripubertal obesity and
associated hyperinsulinaemic hyperandrogenaemia are the
forerunners of PCOS (1115).
Obesity in PCOS patients may be related to problems in
dealing with energy balance with a higher incidence of
eating disorders, reduced postprandial cholecystokinin and
reduced postprandial thermogenesis (1,16,17).
To summarize, the literature contains sufficient evidence
from large retrospective studies to suggest an association
between obesity and infertility, particularly because of ano-
vulation. Obese anovulatory patients may or may not have
PCOS.
Assisted conception in the obese patient
There have been numerous studies with conflicting results
investigating the impact of obesity on in vitro fertilization
(IVF) (Table 2). The majority agree that obese patients need
a higher dose of drugs for ovarian stimulation, have a
higher risk of cycle cancellation and have fewer oocytes
collected. However, there are conflicting results regarding
live birth rates. Several studies have shown that once the
patient reaches the point of embryo transfer, the live birth
rate is no different from patients with a normal body mass
index (BMI) (22,23). Other studies have demonstrated a
lower live birth rate in obese patients (2426) and at least
one study has demonstrated a lower fertilization rate.
Another study has suggested that obesity is associated with
poorer quality oocytes (23). On the other hand, other
studies have shown very little if any effect for obesity on
IVF outcomes (2730).
Another concern is that of impaired drug absorption
after subcutaneous (SC) injection of ovarian stimulation
drugs, because of increased SC fat. However, a study com-
paring the intramuscular (IM) vs. the SC routes for admin-
istration of recombinant follicle stimulating hormone
(rFSH) in obese women found no evidence for a significant
difference in drug pharmacokinetics whether the IM or SC
routes were used (31).
In summary, there is still controversy regarding the effect
of obesity on IVF. However, when taking into consideration
sample sizes of different studies, the results of three par-
ticular studies seem to have the largest impact on the evi-
dence (24,25,32) and have all shown a lower pregnancy
rate in obese patients.
Miscarriage
The relationship between obesity and first trimester miscar-
riage has been extensively investigated (23,26,3538)
(Table 3). Several studies suggest that obesity may increase
the risk of miscarriage (3941) because of adverse influ-
ences on the embryo, the endometrium or both (42).
Although there is a close link between obesity and PCOS,
which is well known to be associated with an increased risk

Table 1 Odds ratio/relative risk (OR/RR) of anovulatory infertility in overweight and obese patients

Study Study design Sample size Population Outcome measure OR/RR 95% CI

Green et al. (18) Retrospective 376 Women with ovulatory infertility Odds of anovulatory infertility 2.1 1.04.3
Jensen et al. (19) Retrospective 28 629 First pregnancies from obstetric Odds of conception per cycle 0.77 0.700.84
database
Grodstein et al. (20) Retrospective 597 Women with ovulatory infertility Odds of anovulatory infertility 3.1 2.24.4
Bolumer et al. (21) Retrospective 4 035 Pregnant women Odds of delayed conception 11.54* 3.6836.15*

*This odds ratio was found in patients who were both obese and smokers. Similar results were not found for obese non-smokers.

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obesity reviews Obesity and female reproduction M. Metwally et al. 517

Table 2 Studies investigating the effect of obesity on IVF outcomes

Study Sample size Study design Main findings

Van Swieten et al. (33)
Linsten et al. (25)
Lashen et al. (27)
Wang et al. (32)
Fedorcsak et al. (24)
Spandorfer et al. (22)
Dechaud et al. (28)
Wattanakumtornkul et al. (29)
Loveland et al. (26)
Wittemer et al. (23)
Fedorcsak et al. (34)
162 IVF/ICSI patients Prospective 45% lower fertilization rates in obese women
8457 IVF patients Retrospective Significantly lower birth rate in women with a BMI 27 kg/m2
(OR 0.67, 95% CI 0.480.94)
333 patients Retrospective Lower peak oestradiol concentration (P = 0.009)
3586 patients Retrospective Significant linear reduction in fecundity from the moderate group
to the very obese group (P < 0.001)
5019 cycles Retrospective Significantly lower cumulative live birth rate in obese group 41.4%
(95% CI 32.150.7)
BMI positively correlated with the dose of gonadotrophins
BMI negatively correlated with the number of collected oocytes
920 patients Retrospective Higher cycle cancellation compared with non-obese
(14.9% vs. 9.1%, P = 0.03)
Lower response to ovarian stimulation
789 cycles Retrospective Higher dose gonadotrophins needed (P = 0.0003)
Similar cancellation rate, implantation rate, and pregnancy rates
in obese and non-obese patients
97 patients Retrospective No difference in implantation rates between obese and non-obese
recipients, OR 1.1, 95% CI 0.52.4
180 IVF cycles Retrospective Significantly lower implantation and pregnancy rates in patients
with a BMI >25 kg/m2
398 patients Retrospective Obese women needed more gonadotrophins for stimulation, had
less oocyte collected but had similar pregnancy and miscarriage
rates to non-obese patients
383 patients Retrospective Obese patients had fewer oocytes collected and a lower live birth
rate

IVF, in vitro fertilization; ICSI, intracytoplasmic sperm injection; BMI, body mass index.

Table 3 Prevalence of miscarriage in various studies

Study Normal Overweight Obese Odds ratio Study design Population

(%) (%) (%) (95% CI)/
P-value

Hamilton-Fairley et al. (39) 27 60* P < 0.05 Retrospective 100 women with clomifene resistance
undergoing ovulation induction
Fedorcsak et al. (34) 12 22* P = 0.03 Prospective Cohort of 383 patients conceiving after IVF
Bellver et al. (42) 13.3 15.5 38.1* OR 4.0 95% Retrospective 712 cycles of oocyte donation
CI 1.5310.57
Lashen et al. (41) 12.5 14.5* OR 1.2 95% Retrospective 1644 obese women matched with
CI 1.011.46 3288 normal weight controls
Al-Azemi et al. (45) 0 22.7 P = 0.0006 Prospective 270 PCOS women
Winter et al. (35) 18 16 OR 0.83, 95% Retrospective 1196 pregnancies after IVF
CI 0.451.50
Fedorcsak et al. (24) 4.6 5.4 7.8 P = 0.008 Retrospective 5019 IVF/ICSI cycles
Loveland et al. (26) 7.1 20.8 P = 0.13 Retrospective 139 IVF cycles
Roth et al. (43) 22 22.3 P = 0.86 Retrospective 494 patients undergoing ovulation induction, IVF
or intrauterine insemination
Wang et al. (36) 18 22 27% (BMI 3034.9) Retrospective 2349 pregnancies after assisted
31% (BMI = 35) conception
P < 0.05

*Significant difference between the obese and normal weight groups.

Included overweight in addition to obese subjects.

IVF, in vitro fertilization; PCOS, polycystic ovarian syndrome; BMI, body mass index.

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518 Obesity and female reproduction M. Metwally et al. obesity reviews

Table 4 WHO classification of obesity

Treatment of obesity to improve
BMI reproductive function

Normal 18.524.9 Weight loss should be considered a first option for obese
Pre-obese 25.029.9 infertile women, where a small decrease in the BMI may be
Obesity class I 30.034.9 accompanied by a dramatic improvement in reproductive
Obesity class II 35.039.9 performance (65).
Obesity class III 40

BMI, body mass index. Physical activity

Although there is little evidence to support the recommen-
Table 5 Maternal and foetal complications of obesity dation of a fixed programme of daily physical activity, it
seems that moderate intensity activity for about 4560 min
Maternal complications Perinatal complications
per day is required to prevent the transition to overweight
Hypertension Intrauterine death
or obesity while 6090 min of moderate intensity activity
Pre-eclampsia Birth weight above the 90th centile or lesser amounts of vigorous intensity activity is needed
Venous thromboembolism Congenital anomalies to prevent weight gain in formerly obese individuals
Gestational diabetes mellitus 1. Cardiovascular defects (66).
Higher incidence of induction 2. Renal defects
of labour
Emergency caesarean section 3. Neural tube defects Diets
Anaesthetic problems Higher risk of adult obesity
Genital tract infections Neonatal hypoglycaemia Very low-caloric diets are effective in short-term weight loss
Urinary tract infections Meconium aspiration but have a questionable role in long-term maintenance
Wound infections Higher risk of induction of labour
(56).These diets can also lead to significant improvement in
Lactation problem Higher risk of failed trial of labour
after caesarean section
free testosterone concentrations, LH/FSH ratio and fasting
Birth injuries insulin levels of obese PCOS patients (67). Low-energy
Shoulder dystocia high-protein diets have also been shown to have compa-
rable effects to low-caloric diets (68,69) and several studies
have even shown that they may have preferable metabolic
of miscarriage, it seems that obesity may act as an indepen- effects (70,71). More studies are needed regarding the diet
dent risk factor for spontaneous miscarriage (42). On the that is best suitable for obese infertile women includ-
other hand, other studies have found no association ing ovulation and pregnancy rates as primary outcome
between miscarriage and obesity (26,27,35,43). measures (Table 6).
Generally, these studies lack consistency mainly because
of the use of different obesity classification systems and Pharmacological agents
future studies should adhere to the WHO classification
system to avoid this problem (44) (Table 4). The evidence is Ovulation induction
therefore far from conclusive and further research is
required. Drugs used to induce ovulation in obese women include
clomifene citrate and metformin as first-line therapy and
FSH as a second-line agent.
Obstetric complications
Clomifene is an oral antioestrogen that raises the serum
The obstetric complications of obesity have probably levels of FSH leading to follicular growth (76). Body fat
received the most attention in the literature. These compli- distribution can affect response to clomifene, and therefore
cations have been extensively discussed elsewhere in the obese patients can be more resistant to clomifene than
literature (1,4664), and a summary of these problems can non-obese (77).
be seen in Table 5. Metformin has recently been reviewed in randomized
It is therefore recommended that obese women should controlled trials as an alternative to clomifene but its exact
receive pre-conception counselling regarding the associated role remains to be established.
risks together with appropriate anaesthetic and dietary Some studies have shown a beneficial effect especially in
input early in the pregnancy (57). Caloric regulation for patients with clomifene resistance (7881). However, two
these women during pregnancy should follow the same recently published randomized controlled trials have
guidelines that govern the amount and types of carbohy- shown that metformin therapy may not be as effective as
drates and fat in non-pregnant women (58). previously thought (82,83).

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obesity reviews Obesity and female reproduction M. Metwally et al. 519

Table 6 Summary of the results of different dietary studies

Study Type of diet Design Sample Main findings

size

Mathus-Vliegen (72) Very low calorie diet (VLCD) Multicentre double-blind, 189 VLCD may have limited value in
parallel-group trial maintaining weight loss
Mavropoulos et al. (67) Low-carbohydrate ketogenic diet Cohort study 11 Significant improvement in
Weight
Free testosterone
LH/FSH ratio
Fasting insulin
Stamets et al. (68) Low-energy high-protein diet vs. RCT 35 No evidence for a difference
low-energy high-carbohydrate diet between the two diets
Piatti et al. (70) Low-energy high-protein diet vs. RCT 25 Improvement of insulin resistance
low-energy high-carbohydrate diet with the high-protein diet
Skov et al. (69) Low-fat high-protein diet vs. low-fat RCT 65 Better weight loss with the high protein diet
high-carbohydrate diet
Farnsworth et al. (71) High-protein vs. standard protein RCT 66 Reduced post load glucose and fasting
low-energy diet triacylglycerol concentrations with the
high-protein diet
Moran et al. (73) High-protein vs. low-protein diet RCT 28 Minor endocrine and metabolic advantages
for the high-protein diet
Douglas et al. (8) Eucaloric MUFA vs. eucaloric Cross-over study 10 Lower fasting insulin levels after the
low-carbohydrate diet low-carbohydrate diet
Samaha et al. (74) Low-carbohydrate vs. low-fat diet RCT 132 More weight loss and more improvement
of insulin sensitivity in the low-carbohydrate
group
Kasim-Karakas et al. (75) Poly unsaturated fatty acid diet Cohort 17 Higher fasting glucose levels
No change in sex steroid hormone profile

LH, luteinising hormone; FSH, follicle stimulating hormone; RCT, randomized controlled trial; MUFA, monounsaturated fatty acids enriched diet.

There is also controversy regarding the effect of the BMI
on metformin therapy. Some studies have shown that
non-obese patients respond better (84), while others have
shown an opposite effect (85).
Similarly several studies have shown that metformin may
produce some degree of weight loss (8688) while others
have not shown any effect (89,90). The current evidence also
suggests that metformin is safe during pregnancy and may
decrease the risk of miscarriage in obese patients (9193).
Anti-obesity drugs
These drugs fall into two classes, centrally and peripherally
acting. The sole representative of the peripherally acting
group is orlistat, and of the centrally acting drugs, sibutra-
mine is the most commonly used.
Orlistat inhibits gastric and pancreatic lipase, thus
decreasing fat absorption from the intestinal lumen by
about 30% (94,95). It is fairly well tolerated, although the
main side effect of gastrointestinal disturbances may limit
patient compliance (96). Compared with metformin, orl-
istat has been shown to produce similar reduction in test-
osterone levels in PCOS patients (86).
Sibutramine acts by inhibiting serotonin and norepineph-
rine reuptake increasing satiety and energy expenditure
(97,98). Compared with metformin, sibutramine can cause
a greater reduction in insulin levels and insulin resistance
(87).
More recently, rimonabant, a selective cannabinoid-1
receptor blocker, has been licensed in the UK. Studies are
still sparse but show it to be effective in reducing body
weight and improving metabolic profiles (99).
It is paramount to consider the safety of these drugs
should a woman conceive while receiving them. Based on
the manufacturers advice, both rimonabant and sibutra-
mine are contraindicated in pregnancy. However, one
recent study involving 52 pregnant women exposed to
sibutramine in the first trimester showed no evidence of
congenital anomalies in their neonates. Seven women,
however, developed hypertensive complications during
pregnancy (100).
Evidence regarding the safety of orlistat in pregnancy is
also lacking and the manufacturer advises caution.
However, orlistats pharmokinetics place it in a favourable
position compared with other drugs, because of the very
low-absorption and first-pass metabolism resulting in a
bioavailability of less than 1% (95). In conclusion, further
studies are needed before sound recommendations can be
made regarding the use of these drugs in women attempting
conception.

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520 Obesity and female reproduction M. Metwally et al.
Bariatric surgery
Weight reduction or bariatric surgery remains an option for
those who fail to lose weight by other means. The guide-
lines of the National Institute for Health and Clinical
Excellence state that surgery is recommended for people
with a BMI of 40 kg m-2 or 35 kg m-2 in the presence of
a significant comorbidity that can be improved by weight
loss.
Laparoscopic adjustable gastric banding (LAGB) is one
of the most popular procedures. The tightness of the band
can be adjusted for the altered nutritional requirements of
pregnancy but this may compromise the weight loss. There-
fore, until the target weight is reached, a method of
contraception should be used (101).
Regarding safety with pregnancy, LAGB has been shown
to be well tolerated and associated with a lower incidence
of gestational diabetes and hypertension (102) and favour-
able fetal outcomes (103106). Some studies, however,
have shown an increased risk of miscarriage when preg-
nancy occurs soon after the procedure (107).
The increase in prevalence of obesity makes it likely that
more women will opt for bariatric surgery and so further
studies to establish its impact on reproductive performance
are needed.
To conclude, obesity is associated with a wide range of
adverse reproductive effects. Obese women presenting with
fertility problems also commonly suffer from PCOS which
acts as an important confounding factor. Obesity per se
poses significant adverse reproductive risks regardless of
PCOS and future studies should include study populations
that would provide information on the effects of obesity
alone.
Measures to reduce weight should be recommended
before resorting to costly treatment for infertility as weight
loss is probably as effective as any pharmacological inter-
vention in improving reproductive performance.
Conflict of Interest Statement
No conflict of interest was declared.
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